Repeated Implantation Failure (RIF)

    Last updated date: 03-Mar-2023

    Originally Written in English

    Repeated Implantation Failure (RIF)



    Repeated Implantation Failure

    Repeated embryo implantation failure (RIF) is a very frustrating disease for both patients and professionals, and treating it is one of the most challenging issues in the area of in vitro fertilization (IVF). Uterine anatomic abnormalities, thrombophilia, non-receptive endometrium, and immunological variables are examples of maternal factors. 

    Failure to implant owing to embryonic reasons is related with either genetic defects or other embryonic factors that impede the embryo's capacity to grow in utero, hatch, and implant. New methods of time-lapse imaging of embryos and assessing their metabolic activities may enhance embryo selection and subsequent results for IVF patients and those diagnosed with RIF.


    What is Repeated Implantation Failure (RIF)?

    Repeated Implantation Failure

    When embryos of excellent quality fail to implant after numerous in vitro fertilization (IVF) treatment cycles, this is referred to as repeated implantation failure (RIF). Implantation failure is caused by either maternal or embryonic factors.

    Implantation comprises two basic components: a viable embryo with the capacity to implant and a receptive endometrium with the ability to implant. The "cross-talk" between the embryo and the endometrium, which eventually leads to embryo apposition, attachment, and invasion, is required for successful implantation and appropriate placentation. These pathways are being thoroughly investigated and appear to involve various mediators originating in the embryo as well as the endometrium, as well as the maternal immune system.

    Any abnormalities in the embryo, endometrium, or immune system will lead to implantation failure. As a result, while evaluating RIF, the embryo should be examined in relation to the uterus and its functioning endometrium. As a result, RIF therapy should focus on the discovered irregularity and the repair of any probable defect that may lead to implantation failure.


    Common causes of repeated implantation failure

    causes of repeated implantation failure

    Because factors linked to one or both parents might contribute to recurrent implantation failure, we will often undertake a battery of tests to examine and discover the cause.

    • The quality of the egg or sperm
      A high-quality egg and sperm are required for a healthy embryo. Given that healthy embryos have the best chance of implanting in the womb, it is critical to utilize the finest quality eggs and sperm feasible during IVF. Unfortunately, a variety of circumstances can impair egg and sperm quality.

      Age has a significant impact on egg quality (and quantity). Egg quality often diminishes beyond the age of 35 in women. This indicates that eggs taken from elderly women have a lower chance of successfully implanting in the uterine wall.

      Recurrent implantation failure can also be caused by sperm abnormalities. For example, damage to sperm genetic material, commonly known as DNA fragmentation, might impact embryo development and hence the chance of implantation. Smoking, alcohol consumption, and being overweight, as well as several underlying medical disorders and prescription drugs, can all harm the DNA in sperm and eggs.

      While there is no test to measure egg quality, while doing a semen study, we can check for greater than usual amounts of sperm DNA fragmentation.

    • Chromosomal anomalies in the embryo
      Chromosome variations inside the embryo are a key cause of recurrent implantation failure. Chromosomes are DNA-containing unique structures found within cells. Normally, each egg and sperm contain 23 DNA-containing chromosomes, and all 23 are passed on from each parent during conception (giving the embryo a total of 46 chromosomes).

      However, chromosomal mistakes can occur during the embryonic development process. This includes aneuploidy (abnormalities in the number of chromosomes present) and structural modifications that affect the size of chromosomes or how the DNA is organized inside them. The quantity of genetic material contained in the embryo may also rise. Chromosomal abnormalities inside the embryo, regardless of the kind of defect, are far less likely to result in a continued pregnancy.

      Female age is the most significant contributor to chromosomal abnormalities in the embryo. A person can, however, be born with a structural rearrangement in their own chromosomes, which can predispose them to generating predominantly defective eggs or sperm. A karyotype test on the persons donating the egg and sperm can discover this.

      If we suspect chromosomal mistake, we can check an embryo's chromosomal layout using pre-implantation genetic testing before transfer.

    • The environment of the uterus
      The endometrium (the tissue that forms on the inside lining of the uterus) must undergo biological changes in order for an embryo to effectively implant in the uterus. The endometrium thickens and becomes receptive to prospective embryo implantation in preparation for a healthy embryo.

    • Why might I have a “non-receptive” uterus?
      If the uterus contains adhesions, polyps or fibroids in the cavity, then its receptivity will be impaired.

      If progesterone levels rise prematurely (that is, before egg collection owing to early Latinization of follicles) during an IVF cycle, the uterus' receptivity does not coordinate well with the moment of embryo transfer. This can result in a failure implantation. This issue can be resolved by closely monitoring the IVF cycle.

      It is believed that thin endometrial lining (a lining which is less than 8mm) is not receptive enough.

      An infection of the uterus has also been hypothesized to prevent implantation, by making the uterine environment less optimal.

      Imaging investigations and surgical procedures can assist us in determining whether an inflammatory disorder is harming the uterine environment. Pelvic ultrasonography and the implantation of a camera via hysteroscopy or laparoscopy are two examples.

    • Lifestyle factors and medical conditions
      One or both parents' health and lifestyle choices can have an influence on the success of embryo transfer. Diabetes, thyroid illness, and other endocrine diseases, as well as autoimmune disorders and clotting disorders (e.g., thrombophilia), can all interfere with the interaction of the embryo with the endometrium in the mother. Furthermore, both parents' alcohol intake, smoking, and other modifiable lifestyle variables (such as poor nutrition, lack of exercise, and being overweight) may contribute to repeated implantation failure by reducing egg/sperm quality and the health of the uterine environment.


    Improving the success of embryo transfer

    Improving the success of embryo transfer

    To increase the odds of the embryo implanting in the uterine wall, our embryo transfer approach is designed to preserve the embryo while also assisting it in reaching its goal. A delicate tube known as a catheter transports the embryo from the incubator to the uterus. Along the journey, we use ultrasound imaging to ensure that the embryo is precisely placed.

    We also place the embryo in a special material called EmbryoGlue before transfer to increase the odds of it implanting in the uterus. EmbryoGlue includes hyaluronan, a uterine substance that may aid in the attachment of the embryo to the uterine wall.


    What can I do if I have repeated implantation failure?

    repeated implantation failure

    1. Check your AMH, FSH and E2 levels on day 3, and antral follicle count to see whether they are normal. Do you have a healthy ovarian reserve? If you have little ovarian reserve, are over 40, and have had many implantation failures, you should consider utilizing donor eggs.
    2. If you are young and have good ovarian reserve, ask the embryologist about the quality of your embryos. If they are of excellent quality (dividing well for their age), the embryos that were transplanted are likely to be genetically normal (sadly, we still do not have the technology to test for all possible genetic defects before the transfer).
    3. Do you suffer from PCOS? Did they extract a large number of eggs (more than 25 eggs) from your ovaries? PCOS may be to blame for the absence of embryo implantation. Metformin and myoinositol, which are insulin sensitizers, may help you.
    4. You can attempt various ovarian stimulation protocols if your doctor has used the same ovarian stimulation technique to retrieve eggs from your ovaries. Mild ovarian stimulation procedures have been shown to produce higher quality eggs and embryos in a subgroup of IVF patients (mostly patients with poor ovarian reserve).
    5. If you have previously failed IVF with a day 3 embryo transfer, attempt a day 5 embryo transfer. The fact that your embryos are maturing to the blastocyst stage is a good sign (but not conclusive proof) that your embryos are viable.
    6. Instead of a fresh transfer, you might consider a frozen embryo transfer. High estrogen levels in the body during a new cycle might harm uterine receptivity.
    7. If you have cervical stenosis and embryo transfer via the cervical route becomes problematic, you might attempt other methods (like ZIFT)
    8. You can try changing the clinic – sometimes this works!
    9. Another option available is to use donor eggs or donor embryos.
    10. You must remove any adhesions, polyps, or fibroids in your uterine cavity. Surrogacy may be an option if you have a lot of adhesions or a thin uterine lining due to untreatable Asherman's syndrome.


    Can Implantation failure be treated?

    Implantation failure treatment

    Yes, it is treatable, but only if the cause is recognized. Genetically incompetent embryos are the only well-known, scientifically validated cause of implantation failure. If you are a woman of advanced maternal age or have early ovarian aging, even if you are able to transfer some embryos during an IVF round, they may be genetically defective and may not implant properly.

    The irony is that many women refuse to accept this truth (after all, it is tough to realize that they cannot produce a genetic baby) and instead blame their uterus for the unsuccessful implantation. As a result, many feel that surrogacy can assist them in conceiving, which is false!

    Doctors take advantage of their ignorance and "treat" patients with a variety of non-evidence-based treatments. I've watched so many ladies of advanced maternal age torture themselves to a slew of ineffective procedures before eventually finding success with donor eggs. If advanced maternal age or a lack of ovarian reserve is the cause of unsuccessful implantation, donated eggs are the only viable option.

    If you have adhesions, fibroids, or polyps in your uterine cavity that are interfering with implantation, eliminating them will assist you achieve embryo implantation. Endometrial thickness's significance in successful implantation is yet unknown. Many women with thin endometrial have successful implantation, although scientific evidence suggests that an endometrium thickness of more than 8mm is optimal for implantation.


    • What kinds of “non-evidence” based therapies are available to treat implantation failure?

    The following therapies do not have solid proof for their efficacy and are very speculative:

      • Use of blood thinners like aspirin and heparin.
      • Causing local injury to endometrium before embryo transfer, to improve local uterine blood flow.
      • Therapies like use of steroids, IVIG, intralipids etc which claim to reduce NK cell levels in the uterus.
      • Paternal lymphocyte immunotherapy to “treat “HLA matching between partners.
      • Use of embryo glue (a substance which is claimed to enhance the attachment of embryo to the uterus).
      • Routinely making a hole in the zona pellucida of the embryo (outer coat of the embryo) with the aim of helping the embryo to hatch out of the shell successfully. This is known as laser assisted embryo hatching.
      • Co-culturing embryos with endometrial epithelial cells.
      • Intrauterine administration of Peripheral Blood Mononuclear Cell (PBMCs).

    Doctors should not recommend such procedures. They must ensure that the patient realizes that the therapies listed above are not evidence-based and may not be a cure-all for their ailment.


    IMSI and HA ICSI

    IMSI and HA ICSI

    Intracytoplasmic Morphologically chosen Sperm Injection (IMSI) is a procedure that we occasionally employ to assist choose sperm for Intracytoplasmic Sperm Injection (ICSI). ICSI may be used to assist fertilization during IVF. During ICSI, a single sperm is isolated and injected into the center of a mature egg, assisting in the removal of any impediments to natural fertilization. In the case of IMSI, we examine all available sperm under a strong microscope before selecting the sperm with the healthiest-looking form and structure to introduce into the egg using ICSI.

    Another approach we occasionally employ to assist choose the best sperm for the ICSI treatment is hyaluronic acid (HA) ICSI, also known as PICSI (Physiological Intracytoplasmic Sperm Injection). Sperm that can adhere to hyaluronic acid (a chemical produced naturally in your body) has minimal levels of DNA fragmentation. Choosing the healthiest sperm raises the odds of a healthy embryo, which has a better chance of implanting.



    Implantation failure

    1. What are the main causes of embryo implantation failure?
      Failure of implantation with IVF can occur owing to egg or sperm quality issues, smoking, poor laboratory culture conditions, and uterine receptivity issues. Fibroid polyps, septum, hydrosalpinges, persistent endometriosis, and poor uterine line development can all cause uterine receptivity issues (thin endometrium).

    2. Does vitamin D affect embryo implantation?
      Although vitamin D has historically been associated with bone health, its possible involvement in fertility is becoming increasingly significant. This hormone, which has receptors in the ovary, endometrium, and placenta, has been associated to reproductive and obstetric outcomes.

      According to research, adequate vitamin D levels increase the likelihood of conception. The process by which the pace of gestation rises, however, is not well understood.

      In a research on donor egg recipients, where it is expected that all embryos would be of acceptable quality, it was shown that patients with adequate vitamin D levels had a higher probability of becoming pregnant. However, this impact was not detected in another investigation including the transfer of euploid (chromosomally healthy) embryos. Thus, while data suggests that vitamin D improves endometrial receptivity, its effect is likely to be more nuanced than it appears at first look.

      Another way that vitamin D may boost pregnancy rates is via enhancing egg quality. Vitamin D levels in blood have been proven to be related to levels in follicular fluid, and it is thought that vitamin D may alleviate ovarian aging, albeit it has not been studied directly in eggs.

    3. Do low progesterone levels cause implantation failure?
      Yes. Progesterone is essential for the maturation of the uterine lining in preparation for embryo implantation. Low levels of progesterone after ovulation (also known as luteal phase deficit) may result in implantation failure.

    4. At how many implantation failures do I know when it's time to resort to egg donation?
      We refer to repeated implantation failure when pregnancy has not happened despite transferring 10 or more excellent quality embryos during the patient's assisted reproductive therapies, or when 3 or more embryo transfers have been performed with good quality embryos.

      The embryo and the endometrium are required for implantation. As a result, both should be evaluated.

    5. What are the main causes that hinder embryo implantation in an ART cycle?
      There are several types of causes that can hinder the correct implantation of the embryo:
      1. Uterine problems. The presence of uterine disease can influence embryo implantation. Before undergoing a reproduction therapy, it is usually necessary to rule out the presence of the same (polyps, myomas, intrauterine adhesions, etc.).
      2. The intrinsic quality of the embryos transferred. Higher quality embryos are more likely to implant.
      3. Issues resulting from the administration of assisted reproduction therapy. The most obvious example is a substantial increase in blood estradiol levels (more than 3000 pg/mL).
    6. Which treatment is the most effective for a successful embryo implantation?
      The optimum therapy is one that produces high-quality embryos with no conditions that reduce their chances of implantation. Furthermore, it is vital to rely on the proper transport of the identical ones to the inside of the uterus.

      It is important to note that, thanks to significant advances in cryobiology (vitrification of oocytes and/or embryos), it has now been achieved that the negative impact that circumstances derived from controlled ovarian hyperstimulation can have is minor, given that the transfer of the embryos to a natural cycle can be postponed instead of transferring in circumstances of high levels of estrogens, a more physiological environment for embryo implantation and for womb formation.



    The failure of repeated transfers of embryos of excellent morphological quality is referred to as recurrent implantation failure (RIF). In vitro fertilization (IVF) therapies rely heavily on embryo implantation. A successful pregnancy is dependent on the interplay of a good quality embryo and a receptive endometrium. Its failure might be due to embryo quality, anatomical reasons, or immunological causes. The anatomic reasons are a significant issue in RIF, however they are typically treatable. Fibroids, polyps, and adhesions that form as a result of a surgical operation or infection might interfere with the embryo-endometrium attachment process. Furthermore, Mullerian abnormalities and hydrosalpinx might have a deleterious influence on implantation rates and should be considered in RIF patients.

    After three failed attempts, repeat hysteroscopy and blastocyst transfer are strongly advised. There is a room for a modification in the stimulation protocol. In expert hands, AH, PGS, and co-culture are most likely useful. Long-term usage of danazol or GnRH agonists is likely to play a role in endometriosis failures. The use of IVIG is very contentious, yet it may be justified in certain circumstances after several failures. Steroids may have a role in patients with any form of autoimmunity, and ZIFT may have a role in problematic embryo transfers.